A Bone Marrow–Mimetic Hydrogel Enables Dual‐Phase Hemostasis and Vascularized Osteogenesis for Cranial Defects

ABSTRACT Critical‐sized cranial defects present two sequential clinical challenges. These include an acute need for rapid hemostasis and a long‐term requirement for vascularized bone regeneration. Current implants fail to address these sequential demands. To overcome this limitation, a bone marrow‐mimetic composite hydrogel (FE‐PDA@Fib/Gel‐TG) is engineered. This system integrates transglutaminase crosslinked gelatin, rigid polydopamine‐coated hydroxyapatite/poly(L‐lactic acid) (HAp/PLLA) short fibers, and cell‐free fat extract (FE). These components together recapitulate key biochemical and biomechanical features of native bone marrow. The hierarchically designed scaffold immediately achieves hemostasis through fiber‐mediated mechanical sealing and catechol‐assisted clot stabilization. Furthermore, the sustained release of FE establishes a pro‐regenerative microenvironment. This milieu significantly enhances cell recruitment, endothelial network formation, and osteogenic differentiation. It also promotes heterotypic crosstalk between endothelial and osteoprogenitor cells. Transcriptomic analyses reveal that this vascular‐bone coupling is driven by the convergent activation of VEGF/VEGFR‐PI3K‐AKT signaling pathways. In a critical‐sized calvarial defect model, the hydrogel actively steers macrophage polarization toward an anti‐inflammatory phenotype. Consequently, it induces the robust regeneration of morphologically mature, highly vascularized bone tissue. By successfully coupling rapid hemostatic control with spatiotemporally programmed osteo‐angiogenesis, this multifunctional biomimetic platform represents a highly translatable advancement for effective cranial defect repair.